All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Previous studies have suggested that nicotine, an endogenous neurotransmitter and psychoactive component of cigarette smoking, has profound immunological effects (McAllister-Sistilli, C. G., et al., Psychoneuroendocrinology 23:175-187; Sopori, M., Nat Rev Immunol 2:372-377). During ontogeny, nicotine elevates expression of the recombinase-activating gene on developing thymocytes in the thymus (Middlebrook, A. J., et al., J Immunol 169:2915-2924) and regulates B cell development in the bone marrow (Skok, M. V., et al., Life Sci 80:2334-2336). For mature lymphocytes, nicotine suppresses the T cell response and alters the differentiation, phenotype and functions of antigen-presenting cells (APCs) including dendritic cells (Nouri-Shirazi, M., et al., Immunol Lett 109:155-164; Guinet, E., et al., Immunol Lett 95:45-55) and macrophages (Floto, R. A., et al., Lancet 361:1069-1070).
The impact of nicotine on immune responses in vivo, however, is extremely complex depending on the dosage, the duration of exposure as well as the involvement of specific organ systems in which immune responses evolve. Nicotine dampens inflammation and reduces mortality in a mouse model of sepsis (Wang, H., H. et al., Nat Med 10:1216-1221). This compound additionally reduces the incidence of type 1 diabetes in mice (Mabley, J. G., et al., J Pharmacol Exp Ther 300:876-881) and alters humoral autoimmunity in the experimental model, systemic lupus erythematosus (SLE) of mice (Rubin, R. L., et al., Toxicol Sci 87:86-96). Several epidemiological studies reveal a strong inverse correlation between smoking and the autoimmune response, the clinical manifestations of SLE and ulcerative colitis (Rubin, R. L., et al., Toxicol Sci 87:86-96; Jani, N., et al., Gastroenterol Clin North Am 31:147-166). Other studies suggest that smoking might be associated with the exacerbation of multiple sclerosis (MS) and Crohn's disease (Emre, M., et al., Arch Neurol 49:1243-124; Friend, K. B., et al., Disabil Rehabil 28:1135-1141; Johnson, G. J., et al., Aliment Pharmacol Ther 21:921-931). Confounding factors conferring disease exacerbation, as well as dosage and duration of smoking in these studies likely contribute to the discrepancy observed between the possible positive vs. negative effects of nicotine.
Inflammatory and immune responses within the central nervous system (CNS) are capable of shaping the clinical outcome of CNS diseases including stroke, trauma, Alzheimer's disease, Parkinson's disease, epilepsy, encephalomyelitis and MS (Zipp, F., et al., Trends Neurosci 29:518-527). Compared to other organ systems, the CNS has several unique properties with respect to immune responses. First, the spectrum of APCs differs from that in the periphery, because in the CNS, resident microglia and astrocytes are active participants (Ponomarev, E. D., et al., J Immunol 178:39-48; Simard, A. R., et al., Mol Psychiatry 11:327-335). Second, cells from the periphery that migrate into the CNS encounter myelin and other antigens, then undergo reactivation enhancing their capacity to recognize a wide spectrum of ambient antigens, a process defined as determinant spreading (McMahon, E. J., et al., Nat Med 11:335-339). Third, given the physical proximity of neuronal cells, the nature and magnitude of immune responses within the CNS are likely influenced by signals stemming directly from the local environment. Despite the quite extensive literature on the impact of nicotine on immune responses in various organ systems, the influence of nicotine on CNS inflammation has not been investigated.
Accordingly, there is a need in the art for greater understanding of the role of nicotine in CNS inflammation, as well as a need to develop novel methods of treatment for conditions associated with CNS inflammation and autoimmunity.